This renewal application represents a multidisciplinary approach to study the mechanisms that regulate metabolic activities and differentiating events in the developing central nervous system (CNS). The previous grant support has been instrumental in establishing that various neural cell types have markedly different neurochemical and physiological profiles and that these differences require unique patterns of interactions and metabolic exchanges between glial and neuronal cells. We hypothesize that alterations in these interactions and/or exchanges will contribute to abnormal neural function that will be manifested as mental retardation. Therefore, the proposed studies will focus upon basic questions of substrate transport, enzyme activities, precursor-product relationships, membrane structural components and neurotransmitter-receptor interactions. The four projects address one or more aspects of this research theme both as individual investigations and as collaborative efforts. The emphasis of project one will be the role of branched chain amino acids in the glutamine-glutamate axis in the brain using new techniques developed in this laboratory. The second project will focus on intracellular exchanges, carrier mediated transport, compartmentation and the regulation of enzyme activities of "trafficking" metabolites such as alanine, malate and lactate. A third project uses molecular biological and cell pharmacological techniques to elucidate the role of GABA-A receptors in mediating trophic responses during early brain development. The fourth project will determine the role of the structural protein "Spectrin" in the formation specialized membrane domains in developing CNS. The results of this integrated, multidisciplinary approach should enhance our understanding of the complex CNS matrix and the varied metabolic and differentiating events which when altered give rise to many types of mental retardation. They will also provide guidance for the clinical management of infants with developmental disabilities.